The research described in this proposal may be divided into two parts. The first deals with mechanisms of action of several drugs on their ability to protect rabbits from the lethal effects of arachidonic acid. Arachidonic acid, given intravenously, is highly lethal to rabbits, presumably through its rapid bioconversion to thromboxanes which precipitate platelet aggregation. The platelet plugs then lodge in the microvasculature of the lung and produce massive pulmonary thrombosis. We have found that several of the MAO inhibitors protect animals from the lethal effects of arachidonic acid, and this appears to be related to their ability to inhibit platelet aggregation. We are in the process of studying which of the MAO inhibitors are effective and how they exert their protective effect. The research to date indicates an inhibitory effect on the biosynthesis of the thromboxanes. Recently, we found that the hormone, thyrotropin releasing hormone (TRH), administered into the lateral ventricles of the brain, also protected animals from arachidonic acid injections. We have not yet determined the mechanism of this phenomenon, but feel that TRH releases some factor which inhibits platelet aggregation. These studies are currently in progress. The second area of research also deals with TRH. During the past year we have found powerful analeptic and respiratory stimulant properties of TRH when administered in the brain ventricles. These effects are especially noticeable in the animal whose respiration is severely depressed with anesthetic doses of barbiturates. We plan to characterize and clarify the mechanism of these actions of TRH and to determine its possible role in the regulation of respiration. BIBLIOGRAPHIC REFERENCES: Lowe, M.D., Reichenbach, D.D., and Horita, A.: Extraneuronal monoamine oxidase in rat heart: Biochemical characterization and electron microscopic localization. J. Pharm. Exp. Therap. 194: (3): 522-536, 1975. Influence of TRH on drug-induced narcosis and hypothermia in rabbits. Horita, A., Carino, M.A., and Chesnut, R. In Press, Psychopharmacologia, 1976.